Potent and Highly Selective Inhibitors of the Proteasome Trypsin-like Site by Incorporation of Basic Side Chain Containing Amino Acid Derived Sulfonyl Fluorides

Journal of Medicinal Chemistry
Raik ArtschwagerRob M J Liskamp

Abstract

A unique category of basic side chain containing amino acid derived sulfonyl fluorides (SFs) has been synthesized for incorporation into new proteasome inhibitors targeting the trypsin-like site of the 20S proteasome. Masking the former α-amino functionality of the amino acid starting derivatives as an azido functionality allowed an elegant conversion to the corresponding amino acid derived sulfonyl fluorides. The inclusion of different SFs at the P1 site of a proteasome inhibitor resulted in 14 different peptidosulfonyl fluorides (PSFs) having a high potency and an excellent selectivity for the proteolytic activity of the β2 subunit over that of the β5 subunit. The results of this study strongly indicate that a free N-terminus of PSFs inhibitors is crucial for high selectivity toward the trypsin-like site of the 20S proteasome. Nevertheless, all compounds are slightly more selective for inhibition of the constitutive over the immunoproteasome.

References

Oct 29, 2003·Cancer Control : Journal of the Moffitt Cancer Center·Paul G RichardsonKenneth C Anderson
Jul 10, 2007·Cancer Research·Susan D DemoMark K Bennett
Dec 17, 2009·Nature Reviews. Immunology·Marcus GroettrupMichael Basler
Aug 24, 2011·Nature Reviews. Molecular Cell Biology·Allan M WeissmanAaron Ciechanover
Aug 27, 2011·Chemical Reviews·Ayman El-Faham, Fernando Albericio
Jun 26, 2012·Progress in Molecular Biology and Translational Science·Deborah A Ferrington, Dale S Gregerson
Nov 23, 2012·Journal of Medicinal Chemistry·Arwin J BrouwerRob M J Liskamp
Nov 30, 2013·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ayman El-FahamFernando Albericio
Sep 23, 2014·Angewandte Chemie·Christian DubiellaMichael Groll
Jan 27, 2016·Drug Design, Development and Therapy·Barbara MuzAbdel Kareem Azab
Mar 1, 2016·Investigational New Drugs·Jeffrey R InfanteKyriakos P Papadopoulos
Jun 19, 2016·Bioorganic & Medicinal Chemistry·Arwin J BrouwerRob M J Liskamp
May 1, 2015·Chemical Science·Arjun Narayanan, Lyn H Jones

❮ Previous
Next ❯

Citations

Aug 23, 2019·Nature Communications·Ruting XuSaihu Liao
Nov 17, 2020·Angewandte Chemie·Xingliang NieSaihu Liao
Jun 9, 2021·ChemMedChem·Fabian H KnaupFelix Hausch
Jun 24, 2021·Organic Letters·Shuheng Xu, Sunliang Cui
Aug 6, 2021·Chemical Science·Tao ZhongJiang Weng
Jan 19, 2019·Journal of Medicinal Chemistry·Bo-Tao XinHerman S Overkleeft
May 6, 2019·Journal of Medicinal Chemistry·Gaochan WuPeng Zhan

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.